Microbiology: failings and best practice
Microbiological issues in pharmaceutical plants can result in plant shutdowns and products withdrawn from the market. Failures are common in environmental monitoring, media fill, sterilisation, aseptic practice and gowning. Introducing lean practices can determine optimal batch size and lead to a decreased number of test sessions for bioburden, endotoxins and sterility testing, while taking a risk-based approach to determining objectionable micro-organisms may ease the cost and burden of unnecessary testing but requires a better understanding of the processes and risks involved.
Susan Birks reports from the annual Pharmig conference in Nottingham, UK, which revealed how greater understanding of microbial risks has increased the role of testing but also highlighted a need for practice improvements.
Microbiology services are crucial for trouble-free operation in pharmaceutical facilities as microbiological issues can be hugely significant, resulting in plant shutdowns and products withdrawn from the market. Recent recipients of FDA 483 forms show that no company is too big to fail. With this in mind, the two-day Pharmig conference held recently in Nottingham offered several best practice presentations on microbiology. Three presentations have been chosen to highlight some common failings and some of the new methods for achieving improvements for the sector.
Neil Raw, GMP Inspector at the MHRA, highlighted some microbiology-related issues raised during EU GMP Inspections. While microbiological issues do not make it into the top 10 most common failings found during inspections, he said, they do occasionally give rise to concern.
Raw’s talk covered operations such as environmental monitoring, media fill, sterilisation, aseptic practice and gowning, where microbiology failures were common.
The main failings on environmental monitoring, for example, included: sample points not being representative of worst case locations; an absence of documented rationale to support sampling positions; sampling positions not adequately documented; insufficient trending and trends not identified; in-house media overcooked; the incubation of plates in sealed bags (where poor gas exchange may affect growth); and anaerobes not looked for where nitrogen is used.
His over-riding message on environ-mental sampling was that, if the microbiological department has a policy, make sure it has a rationale behind it and that it has been documented.
Looking at problems of contamination, validation and cleaning issues, he said that many microbiology labs are lacking clear procedures of what to do if out of spec results are encountered. “Chemistry labs on the whole have good diagrams and systems for dealing with out of spec results. But in my experience microbiology labs often don’t,” he said. Other failings in this area included: exotic bacteria being identified and then accepted without further questions; the air sampler for aseptic areas being stored in the microbiology lab; or media and incubation conditions not being suitable for testing the growth of fungi.
Failings in the use of media fills and sterilisation practice included non-production personnel not being included in routine media fill programmes; sterilised equipment not being stored in Grade A areas; and sterile and non sterile items not being readily identified.
Inspections of gowning areas picked up the following omissions: no gowning assessments had been undertaken; step-over benches were not disinfected; and gowns were worn outside the production area.
The potential for cross-contamination seen during inspections resulted from errors such as: live cultures being stored next to media in the fridge; non-sterile hand sanitisers being used before entering Grade A/B areas; and staff not removing lab coats when moving between dirty and clean areas.
Problems associated with infrastructure and equipment also give rise to issues. For example, drains and sinks in inappropriate areas and not sanitised or monitored; and clean tanks and containers left damp.
His long and varied list made it clear that breaches of good practice are not rare. To avoid this, specialised training is key and needs to be continuous, the systems in place need to be practical and well understood and breaches made more difficult and obvious.
Valerie Dunne of Pfizer, Grange Castle, Ireland, looked at how lean techniques and operational efficiencies can be applied to microbial labs. The Pfizer labs in question are involved in the testing of bioburden, endotoxins, microbial identification, and viability-, purity- and sterility testing.
Dunne said that as a result of introducing lean practices optimal batch size determination has led to a decreased number of test sessions for bioburden, endotoxins and sterility testing. Workflow mapping has also resulted in improved efficiencies with test sessions. Scheduling optimisation has reduced non-testing preparation activities and gowning by 35%. And “role cards” have been implemented that schedule the activities that need to be performed, allowing for dedicated time for cross-training and project work.
Pfizer partnered with outside consultants to implement lean labs and after initial consultations, teams of QC chemistry and microbiology staff were chosen to be leaders of the operation excellence programme. Training was conducted that included both team and area management.
A first step in the Design and Preparation involved creating a “levelling strategy”. The incoming sampling variability was analysed and a strategy selected to meet the required level of demand quickly. This is achieved by developing repeating sequences of testing (Rhythm Wheels) that move the samples through all the required tests and reviews quickly. This reduces throughput time and incoming samples can then be held in a “levelling queue” at the start of the process. Trains (defined sequence of tests without fixed repeat interval) are also developed. To do this, tasks were separated into routine, non-routine and non-added value techniques. Any constraints on testing were also identified and removed.
Equipped with this strategy, the teams were able to optmise the way the tests were carried out, collect the task times for this, confirm customer demand (such as when the tests were needed) and optimise the tasks for the roles.
The use of role cards was adopted and analysts were trained to carry out all the tasks so that the cards could be rotated. Shift huddles – short routine meetings using visuals such as white boards were introduced to manage and monitor labs and to ensure good communication between shifts. The board could, for instance, list test methods with name, status and action in the columns. Dunne suggested there should be a “parking lot” on the board to show when there are enough samples for “wheels” and “trains” to go. For roles that require more than one day, the white board can show the person who picks up the next day, where to start.
Using simple observation of the movement around test stations during tests led to the removal of unnecessary equipment and all necessary equipment being given a designated location and label.
Other simple practices such as defined location and labelling of samples in sample bins in refrigerators enabled them to be located more quickly. In the microbial identification lab there was a lack of organisation by priority, so a visual management system was created. Samples were stored in designated areas and labelled based on priority and type of sample.
According to Dunne, the process was a big success and saved 5,795 hrs/year. The company was also able to reduce headcount significantly. The challenge, she said, was how to sustain it. This involves both organisational and mindset changes. Staff needed training for multi-skilled roles and supervisors on coaching and improvement. Individual performance also has to be tied into team-based success. “It required a shift in mindset from cycle time to schedule adherence.” She added: “Flexibility is key; do not adhere to the original lean system. If tests change then go back to the beginning.”
Dr Stephen Rawling, principal microbiologist, GSK, looked at taking a risk-based approach to determining objectionable micro-organisms. The risk-based approach to safety regulations is meant to ease the cost and burden of unnecessary testing on companies, but this less prescriptive approach by the regulatory authorities does require a better understanding of the processes and risks involved. The FDA regulations that cover this concept are:
- 21 CFR 211.113 Control of microbiological contamination (a), which calls for appropriate written procedures designed to prevent objectionable micro-organisms in drug products not required to be sterile to be established and followed.
- 21CFR 211.84 testing and approval or rejection of components, drug product containers and closures d(6). This requires each lot of a component, drug product container or closure with the potential for microbial contamination that is objectionable in view of the intended use to be microbiologically tested before use.
- 21 CFR 211.165 testing and release for distribution, which calls for appropriate testing of drug batches in the various dosage forms in which they will be used and following physical or chemical deterioration of the product.
- USP Guideline <1111> Microbiological examination of non-sterile products, which states that the significance of other micro-organisms recovered should be evaluated.
Rawling said that to comply with these regulations and take a risk based approach you need to know what micro-organisms you are looking for; you need a sampling plan (it is no good testing for the sake of it and not understanding why you are doing it); and you need to consider who should be involved in determining whether an organism is objectionable.
The first step is to establish what might be considered to be objectionable organisms to your processes and products. “Generate your own lists of anything that can pose a risk,” he advised. It is crucial that the right people are involved in the process and not just the microbiologist. For example, he suggested that it could involve medical and legal teams; management need to be involved to ensure they understand why the decision is important; and regulatory authorities and quality teams also need to be involved.
The next step is to consider factors such as product use, product nature, the method of application, the user or intended recipient, and the presence of extenuating factors that can make microbes more of a risk, such as the presence of disease or wounds.
Rawling then outlined the four main aspects to the risk assessment: hazard identification, hazard characterisation, risk characterisation and an exposure assessment.
Hazard identification: aims to characterise the importance of the organism to the product and should give the organism’s name, number and prevalence, resistance to intrinsic factors, virulence and toxigenesis.
Hazard characterisation: aims to evaluate the nature of the adverse effect associated with the microbiological hazard. For this, consider the consumer and distinctive sub-groups, the severity of hazard, dose response assessment and hazardous level.
Exposure assessment: evaluates the level of organism at the time of application or consumption. This involves looking at its occurrence in raw materials, the effect of processing, the occurrence of toxins, potential for recontamination after processing, the effect of formulation, packaging, product storage, consumer use, and the effect of an open shelf life.
Finally, whereas the exposure assessment gives the likelihood of exposure to the organism on use of the product and hazard characterisation gives the likelihood of adverse effects on exposure, the risk characterisation is an estimation of the likelihood of adverse effects occurring and their severity based on hazard identification and exposure assessment.
With such complex concepts, Rawling reminded delegates that the important thing was to ensure that the results of the risk assessment accord with common sense and with experience.
For details of future Pharmig meetings & training workshops visit www.pharmig.org.uk.
Subscribe now to Cleanroom Technology to get unrestricted online access to our exclusive content and receive our high quality magazine every month.